Active tuberculosis incidence among treatment failure experienced patients in North Wollow Zone: A multicenter historical cohort

Abstract Background In Ethiopia, tuberculosis (TB) is a significant cause of death among individuals living with HIV, especially in resource‐limited areas and those who have experienced treatment failure. However, there is the paucity of data regarding TB among treatment failures experienced people living with HIV. This study aimed to estimate the rate and identify predictors of tuberculosis among patients who received second‐line treatment in North Wollo, Northeast Ethiopia. Methods A retrospective follow‐up study was conducted on 474 HIV‐infected patients who experienced treatment failure. The study period ranged from January 2015 to September 30, 2021. The incidence of TB was assessed using a Cox proportional hazard regression model, after ensuring that all assumptions were met. Factors associated with active TB were determined by analyzing adjusted hazard ratios and 95% confidence intervals. Results In a study of 474 HIV‐positive patients on second‐line antiretroviral treatment, we found an incidence rate of 3.6% with 17 new cases of TB observed over 4412.4 persons per year (PPY). The overall incidence density rate was estimated to be 0.39 cases per 100 PPY (95% CI: 0.239–0.618). Regarding the occurrence of active TB in second‐line patients, WHO clinical treatment stage (T3 and T4), missed isoniazid preventive therapy had a significantly higher risk (AHR: 13.225, 95% CI: 2.894–60.434, p = 0.001), while being married was associated with a lower risk (AHR: 0.203, 95% CI: 0.045–0.907, p = 0.001). Conclusion A high incidence of active TB was observed shortly after initiating second‐line antiretroviral treatment. Factors such as being in the WHO clinical treatment stage (T3 and T4) and marital status were determinants for active TB. To improve overall survival rates, it is vital to enhance early TB screening and implement effective isoniazid preventive therapy.

People living with HIV (PLHIV) are highly vulnerable to TB, a major cause of mortality for this population (1-3).HIV infection greatly increases the risk of active TB, as it impairs cellular immune function and creates a strong synergy with TB.TB is the leading cause of death among PLHIV, highlighting the critical link between HIV infection and TB. 1,2The decline in the immune system exacerbates the reactivation of latent tuberculosis bacilli in the lungs.In 2012, out of 8.6 million tuberculosis cases, 13% were HIV positive and in 2014, 12% of the 9.6 million new TB cases occurred in individuals with HIV. 3,4According to the WHO 2019 report, TB caused 10.1 million new cases and 1.7 million deaths, making it the leading cause of death from a single infectious agent (9).In Africa, the resurgence of TB is linked to TB-HIV/AIDS connection and a shortage of skilled healthcare personnel, not control program deterioration 5,6 In Africa, TB is the second largest disease burden (25%), following Southeast Asia (44%) (12, 13).Additionally, one-third of HIV-associated deaths are attributed to TB (9, 11).In 2018, approximately 251,000 deaths occurred among HIV-infected individuals due to TB, accounting for 33% of all deaths.8][9] The WHO's recent estimation indicates that the risk of developing active TB disease is 21 times higher in HIV-infected people with a 5-10% annual risk and 51% lifetime risk of developing active TB than those without HIV. 10 2018, there were approximately 37.9 million new HIV infections worldwide.Sub-Saharan Africa alone accounted for 75% of the global HIV/AIDS prevalence.By 2019, tuberculosis (TB) had surpassed HIV/AIDS as the leading cause of infectious agent-related deaths worldwide, with an estimated 10.1 million new cases and 1.7 million fatalities, marking a significant shift before 2020. 11,12In sub-Saharan Africa, incidence rates for children and adolescents are high, with 2,017 cases per 100,000 patient-years (20).The twin epidemic of TB and HIV caused 0.3 million deaths worldwide in 2017, with a lifetime risk increase from 15% to 22% (1).[15] In Ethiopia, 5.9% of HIV-positive patients newly enrolled in ART in 2016 had active TB (22).The country is among the top 10 TB burden countries, contributing to 87% of global TB cases (23).In sub-Saharan Africa, 10%-15% of the population is affected by the twin epidemic, with a 51% case fatality rate and higher lifetime risk compared to those without TB and HIV (1, 2).TB-associated mortality varied by region, with 23.01 cases per 100 person-years in Tigray for adults 16 and 17.15 cases per 100 person-years for children in SNNR regions. 17and declining CD4 count is a proxy indicator for treatment failure experienced by patient d. 18 Co-infection with TB increases the risk of death in HIV-positive patients compared to those without TB (5, 16, 25, 26).0][21] Despite the effectiveness of antiretroviral treatment in reducing deaths from opportunistic infections in PLHIV, TB remains a significant cause of mortality, responsible for one-third of deaths among children living with HI. 10,22 The Ethiopian government aims to reduce TBrelated mortality by 90% and TB incidence by 80% by 2030.However, the high rate of co-infection continues to pose significant challenges for treatment efforts for treatment failure experienced by patients in Ethiopia. 19,23| METHODS

| Study setting
This study was conducted in three public hospitals in the North Wollo Zone of the Amhara region in northeast Ethiopia: Tefera Hailu Memorial General Hospital, Woldia Comprehensive Specialized Hospital, and General Teferea Hailu Memorial Hospital.These hospitals were selected due to their early implementation of second-line antiretroviral therapy (ART) and their catchment population.The study was carried out from February 1 to April 30, 2021.
The study specifically focused on HIV-infected individuals who were on second-line ART between September 2016 and April 2020.

| Study period
The data were collected from patients' charts between February 1 and April 30, 2021.

| Study design
A retrospective follow-up study was conducted in a facility-based setting.

Highlighted
• In this study of 474 HIV-positive patients on second-line antiretroviral treatment were included.
• Incidence rate of 3.6% with 17 new cases of tuberculosis (TB) observed over 4412.4 persons per year (PPY).
• Patients with WHO clinical stages III and IV, being married and missed isoniazid preventive therapy has significant implication for action.
• High incidence of active TB observed shortly after initiating second-line antiretroviral treatment.
• Enhancing early TB screening is significant to improve overall survival rates of cases.

| Source population
The study included all HIV-infected individuals who received secondline ART between September 2016 and April 2020.

| Inclusion criteria
The study included individuals on second-line ART and before Second-line ART started TB cases were excluded.

| Sample size determination
The sample size for this study was determined using the double population proportion formula with EPI-Info software.The variables considered for calculating the sample size were opportunistic infections other than TB.The assumptions used were as follows: P1 (52.1%) represented the percentage of exposed individuals with the outcome, P2 (37.7%) represented the percentage of nonexposed individuals with the outcome, Z α/2 (1.96) corresponded to a 95% confidence interval, and r was set as a 1:1 ratio of nonexposed to exposed.Based on these assumptions, the initial sample size was calculated as 404.Accounting for a 10% nonresponse rate due to incomplete medical records, the final sample size was determined as 445.However, between September 2016 and April 2020, there were a total of 493 HIV-positive individuals 24

| Dependent variables
The study aimed to assess the incidence of tuberculosis (TB) in individuals receiving second-line antiretroviral therapy (ART).The outcome of interest was the occurrence of TB, labeled as an "event" (Event = TB or indicated as = 1), while individuals who did not develop TB were considered censored (censor, indicated as = 0).The analysis focused on the duration until TB development after initiating second-line ART, considering TB occurrence as an event and censoring events such as death, loss to follow-up, medical transfer, and completion of the observation period.

| Independent variable
The study examined several socio-demographic characteristics, including age, sex, residence, educational status, and marital status.

| Operational words
Event: TB infection after second-line treatment of ART started ART drug adherence: Classified as good (>95%), fair (85-94%), or poor (<85%) based on the percentage of drug dosage calculated from the total monthly doses of ART drugs.Anemia: Defined as a hemoglobin level ≤10 mg/dL.

| Data quality control assurance
Data collection for adults aged 20 years involved categorizing weight status as underweight (<18.5),normal (18.5-24.9),and overweight/obese (≥25.0).For children aged 2-19 years, weight status categories were underweight (below the 5th percentile), normal (5% to <85%), and overweight/obese (85% and above).A standardized and pretested checklist was used to extract information from ART registry forms, follow-up forms, and medical history sheets.The checklist prioritized relevant variables from national ART formats.It underwent a preliminary review at Woldia Comprehensive Specialized Hospital, with adjustments made based on feedback. 7,25,26

| Data processing and analysis
The data was cleaned, coded, and entered into Epi-DATA (v4.6.0.2).It was then exported to STATA (v14) for analysis.
Statistical summaries and incidence density rates were calculated to assess TB occurrence.The distribution of time-to-eventwas examined using Kaplan-Meier estimates and log-rank tests to identify significant differences.The Cox proportional hazard assumption was checked through graphical and global tests in the final semi-parametric regression.Variables with a p < 0.25 from the bivariable Cox regression were included in the multivariable analysis.Factors associated with TB incidence were determined based on variables with a p < 0.25 in the final Cox regression model, selected using the smallest information criterion value.

| Socio-demographic characteristics of participants
Out of the total 493 sampled subjects, data were collected from 474 participants, resulting in a card completion rate of 96.15%.
The participants had a median age of 41 years with a standard deviation of ±12.48.A significant proportion of the subjects were aged 40 or above (50.2%)and lived in urban areas (60.5%).Nearly half of the participants were married (46.2%), and the majority (91.8%) had disclosed their HIV status (Table 1).

| Clinical characteristics of treatment failure experienced patients
Approximately 92% received PI-based ART, and 83% had good adherence to SLART.About 17% had a history of OIs during SLART follow-up, while 85% took cotrimoxazole preventive therapy.The majority (63.3%) underwent at least one session of EAC during second-line treatment (Table 2).

| The incidence of TB on second-line treatment
Out of the 474 HIV/AIDS patients observed for a total of 4412.4 person-years (PPY), 17 individuals (3.6%) developed active tuberculosis.The overall incidence density rate (IDR) was estimated at 0.39 per 100 PPY, with a 95% confidence interval of 0.239 to 0.618.Since the Kaplan-Meier survival graph did not cross the half-life (h1/2) time, the median time to develop active TB could not be calculated.outcomes compared to divorced or widowed individuals (Chi2 (1) = 3.51, p = 0.17) (Figure 1).Thus, marital status played a role in determining survival outcomes among individuals undergoing second-line ART treatment (Figure 1).

| DISCUSSION
Among 474 PLHIV with treatment failure, 17 new cases of active TB were reported.The overall incidence rate of active TB was 0.39 cases per 100 PPY, which is lower than previously reported in Addis Ababa, 23,27 Debre Markose, 28,29 Afar region, 30 7.2 in England. 31The difference in protocols for treatment and preventive programs could explain these findings.Additionally, the lower reported incidence of TB could be attributed to variations in follow-up periods, sample size, and participant characteristics compared to previously reported results. 10e inability to calculate the median survival time in this report is attributed to the survival curve not intersecting the median or halflife point (h1/2).This can be attributed to factors such as insufficient follow-up time, censoring, low event rate, and limitations in sample size.These challenges make it difficult to accurately estimate the median or half-life time from the survival curve, often necessitating alternative methods or additional data for more precise estimation 32 and India. 33The difference in outcomes for patients on the secondline regimen may be due to factors such as CD4 count progression, lack of nutritional support, and treatment adherence issues leading to viral resistance and increased susceptibility to opportunistic infections.Variations in follow-up periods and sample size may also contribute to the observed differences.
T A B L E 3 Bi-variable and multivariable Cox-regression for determinants of active second-line treatment was initiated in North Wollo selected hospital in Northeast Ethiopia 2023.
It also considered various clinical and laboratory factors such as WHO clinical stage, CD4 count, viral load, ART regimen, hemoglobin level, functional status, opportunistic infections, ART adherence, cotrimoxazole preventive therapy (CPT) use, isoniazid preventive therapy (IPT) use, TB contact history, and delays in second-line therapy as variables of interest.

Figure 2
Figure 2 illustrates distinct survival patterns for individuals in different WHO clinical stages regarding active TB development (Figure 2).

3. 5 |
Factors associated with TB incidence for second-line treatment cases Cox regression analyses were performed in this study to identify predictors of tuberculosis (TB) incidence.Several factors were examined, including age, virological failure, residence, functional status, hemoglobin level, isoniazid (INH) use, CD4 count, ART adherence, ART regimen, and F I G U R E 1 Kaplan-Meier survival plot for active TB after second line antiretroviral treatment patients.F I G U R E 2 The survival curve difference by WHO treatment stage for active TB incidence and second-line treatment.BIZUNEH ET AL. | 5 of 9 counseling during second-line treatment.The final regression model revealed the following associations with TB incidence: Patients in WHO treatment stages III and IV had a significantly higher risk of TB incidence (AHR: 13.225, 95% CI: 2.894-60.434,p = 0.001).
T A B L E 1 Socio-demographic characteristics of HIV-infected individuals who were on SLART in North Wollo and Waghimira Zone, Northeast Ethiopia, 2021.Clinical characteristics of HIV-infected individuals who were on SLART in North Wollo and Waghimira Zone, Northeast Ethiopia, 2021.